• BMB Reports
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• 제50권6호
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• pp.308-317
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• 2017

Bone morphogenetic protein type 2 receptor (BMPR2) is one of the transforming growth $factor-{\beta}$ ($TGF-{\beta}$) superfamily receptors, performing diverse roles during embryonic development, vasculogenesis, and osteogenesis. Human BMPR2 consists of 1,038 amino acids, and contains functionally conserved extracellular, transmembrane, kinase, and C-terminal cytoplasmic domains. Bone morphogenetic proteins (BMPs) engage the tetrameric complex, composed of BMPR2 and its corresponding type 1 receptors, which initiates SMAD proteins-mediated signal transduction leading to the expression of target genes implicated in the development or differentiation of the embryo, organs and bones. In particular, genetic alterations of BMPR2 gene are associated with several clinical disorders, including representative pulmonary arterial hypertension, cancers, and metabolic diseases, thus demonstrating the physiological importance of BMPR2. In this mini review, we summarize recent findings regarding the molecular basis of BMPR2 functions in BMP signaling, and the versatile roles of BMPR2. In addition, various aspects of experimentally validated pathogenic mutations of BMPR2 and the linked human diseases will also be discussed, which are important in clinical settings for diagnostics and treatment.

• Restorative Dentistry and Endodontics
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• 제32권5호
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• pp.459-468
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• 2007

이 연구에서는 법랑모세포 분화과정에서 APin의 기능을 알아보고자 APin-protein microarray를 시행한 후 치아발생과 관련이 있는 MEF2, Aurora kinase A, BMPR-IB와 EF-hand calcium binding protein을 분석하여 다음과 같은 결과를 얻었다. 1 CMV-APin construct를 transfection하여 APin의 과발현을 유도한 경우에는 MEF2와 Aurora kinase A 둘 모두에서 발현이 현저히 감소한 반면에, APin의 발현억제를 유도한 경우에는 둘 모두 변화가 없었다. 2. APin의 과발현을 유도한 경우에는 BMPR-IB와 EF-hand calcium binding protein 모두에서 발현이 크게 증가한 반면, APin을 발현억제 시킨 경우에는 BMPR-IB는 변화가 없었고, EF-hand calcium binding protein은 현저히 감소하였다. 위의 결과들로 보아 APin 단백질은 MEF2, Aurora kinase A, BMPR-IB, EF-hand calcium binding protein과 상호작용하여 법랑모세포의 분화와 석회화 과정 중에 중요한 역할을 하는 것으로 사료된다.

• 치위생과학회지
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• 제11권1호
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• pp.55-61
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• 2011

최근에 Odontogenic ameloblast-associated protein (ODAM)은 MMP-20의 발현을 조절하여 법랑모세포 분화와 법랑질의 석회화에 중요한 역할을 한다고 보고되었다. 그러나 이에 대한 명확한 기전은 알려져 있지 않다. 그러므로 이 연구의 목적은 법랑모세포 분화와 법랑질의 석회화 과정에서의 ODAM의 생물학적 기능과 신호 전달 경로를 찾고자 하였다. Ameloblast-lineage cells (ALCs)를 이용하여 ODAM 재조합 단백질을 생성하고 ODAM 과발현 (ODAM overexpressing) 또는 ODAM 억제(ODAM silencing) 세포주를 만들었다. 세포들은 2주 동안 분화 배지에서 ODAM 재조합 단백질을 처리한 군과 처리하지 않는 군으로 나누어 배양하였다. ODAM의 신호 전달 경로를 확인하기 위하여, ALCs에 BMP2와 BMP receptor 1B (BMPR-1B) 억제제인 BAMBI 재조합 단백질을 처리하였고, 또한 BMPR-1B siRNA 이용하여 BMPR-1B의 발현을 억제하였다. 단백질 발현은 western blot 이용하여 분석하였다. 석회화는 sense ODAM 과발현 세포와 ODAM 재조합 단백질을 첨가한 법랑모세포 세포주에서 증진되었다. 또한 ALP 활성화는 sense ODAM 과발현 세포와 ODAM 정제된 단백질를 첨가한 법랑모세포 세포주에서 뚜렷하게 증진되었다. 기관발생과 관련이 있는 BMPR-IB와 석회화 과정과 관련된 CBP2는 ODAM 과발현을 유도한 경우에는 발현이 증가되었으나, ODAM 발현을 억제시킨 경우에는 발현이 현저히 감소하였다. 이상 실험의 결과는 법랑질 형성과정에서 ODAM이 법랑질 석회화를 증진시킬 수 있음을 시사한다.

• Asian-Australasian Journal of Animal Sciences
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• 제26권1호
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• pp.36-42
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• 2013

The average twin lambing rate of Bayanbulak sheep is 2% to 3%. However, a flock of sheep with a close genetic relationship and an average of 2 to 3 lambs per birth has been found recently. To determine the major genes controlling the prolificacy of the flock in the present study, the flock was designated A while 100 normal Bayanbulak sheep were randomly selected to comprise the control flock B. Ligase detection reaction method was applied to detect and analyze the 10 mutational loci of the 3 candidate prolificacy genes including bone morphogenetic protein type I receptors, bone morphogenetic protein 15, and growth differentiation factor 9. The 10 mutational loci are as follows: FecB locus of the BMPR-IB gene; $FecX^I$, $FecX^B$, $FecX^L$, $FecX^H$, $FecX^G$, and $FecX^R$ of the BMP15 gene; and G1, G8, and FecTT of the GDF9 gene. Two mutations including BMPR-IB/FecB and GDF9/G1 were found in Bayanbulak sheep. Independence test results of the two flocks demonstrate that the FecB locus has a significant effect on the lambing number of Bayanbulak sheep. However, the mutation frequency of the G1 locus in GDF9 is very low. Independence test results demonstrate that the GDF9 locus does not have a significant impact on the lambing performance of Bayanbulak sheep. Among the 10 detected loci, BMPR-IB/FecB is the major gene that influences the high lambing rate of Bayanbulak sheep.

• 대한소아치과학회지
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• 제29권3호
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• pp.345-353
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• 2002

Bone morphogenetic proteins(BMPs)는 형태형성 및 세포 분화동안 다양한 조절 역할을 담당하는 신호전달 인자이다. 시상두개봉합부 발생시 BMPs와 그 수용체의 역할을 분석하기 위해, in situ hybridization방법을 이용하여 태생 15일에서 18일 시상두개봉합부에서 그 발현 양상을 분석하였다. BMP-2와 BMP-3은 태생 15일부터 osteogenic front와 두정골에서 발현을 보였으며 태생 16일부터 모낭에서 발현이 시작되었다. BMP-4는 osteogenic front에서 강하게 발현되었으며, 간엽조직 및 두정골에서 약하게 발현되었다. BMP-5는 모낭에서 발현되었다. 이전 연구에서 BMP-6는 비후된 연골세포에서 발현된다고 보고되었으나 본 연구에서는 발현되지 않았다. BMP-7은 태생기에 두정골에서 발현되었다. BMPR-IB는 osteogenic front의 외측 가장자리에서 발현되었으나, BMPR-IA는 발현되지 않았다. 이런 결과를 종합해 볼 때, 두개봉합부 초기 형태발생시 BMP-4는 미분화 간엽세포로부터 골아세포로 commit되는 초기단계에 중요한 역할을 하며, BMP-2와 BMP-3는 전구 골아세포에서 골아세포로의 분화과정에, BMP-7은 좀 더 분화가 진행된 골아세포 및 골의 분화 유지에 중요하며, type I 수용체 중 BMPR-IB가 BMP들의 신호전달에 중요한 역할을 함을 예측 할 수 있다. 결론적으로 BMP 신호전달은 다양한 BMP 리간드들과 그 수용체들에 의해 골아세포 분화 전반에 걸쳐 관여하고 있음을 시사한다.

• Asian-Australasian Journal of Animal Sciences
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• 제32권7호
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• pp.949-955
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• 2019

Objective: The present study was to investigate the association of polymorphisms in exon-9 of the bone morphogenetic protein receptor-1B (BMPR-1B) gene (C864T) with litter size in 240 Dorset, 232 Mongolian, and 124 Small Tail Han ewes. Methods: Blood samples were collected from 596 ewes and genomic DNA was extracted using the phenol: chloroform extraction method. The 304-bp amplified polymerase chain reaction product was analyzed for polymorphism by single-strand conformation polymorphism method. The genotypic frequency and allele frequency of BMPR-1B gene exon-9 were computed after sequence alignment. The ${\chi}^2$ independence test was used to analyze the association of genotypic frequency and litter size traits with in each ewe breed, where the phenotype was directly treated as category. Results: The results indicated two different banding patterns AA and AB for this fragment, with the most frequent genotype and allele of AA and A. Calculated Chi-square test for BMPR-1B gene exon-9 was found to be more than that of p value at the 5% level of significance, indicating that the population under study was in Hardy-Weinberg equilibrium for all ewes. The ${\chi}^2$ independence test analyses indicated litter size differences between genotypes was not the same for each breed. The 304-bp nucleotide sequence was subjected to BLAST analysis, and the C864T mutation significantly affected litter size in singletons, twins and multiples. The heterozygosity in exon-9 of BMPR-1B gene could increase litter size for all the studied ewes. Conclusion: Consequently, it appears that the polymorphism BMPR-1B gene exon-9 detected in this study may have potential use in marker assisted selection for litter size in Dorset, Mongolian, and Small Tail Han ewes.

• BMB Reports
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• 제55권11호
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• pp.565-570
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• 2022

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease whose pathogenesis is associated with a phenotypic switch of pulmonary arterial vascular smooth muscle cells (PASMCs). Bone morphogenetic protein (BMP) signaling and potassium two pore domain channel subfamily K member 3 (KCNK3) play crucial roles in PAH pathogenesis. However, the relationship between BMP signaling and KCNK3 expression in the PASMC phenotypic switching process has not been studied. In this study, we explored the effect of BMPs on KCNK3 expression and the role of KCNK3 in the BMP-mediated PASMC phenotypic switch. Expression levels of BMP receptor 2 (BMPR2) and KCNK3 were downregulated in PASMCs of rats with PAH compared to those in normal controls, implying a possible association between BMP/BMPR2 signaling and KCNK3 expression in the pulmonary vasculature. Treatment with BMP2, BMP4, and BMP7 significantly increased KCNK3 expression in primary human PASMCs (HPASMCs). BMPR2 knockdown and treatment with Smad1/5 signaling inhibitor substantially abrogated the BMP-induced increase in KCNK3 expression, suggesting that KCNK3 expression in HPASMCs is regulated by the canonical BMP-BMPR2-Smad1/5 signaling pathway. Furthermore, KCNK3 knockdown and treatment with a KCNK3 channel blocker completely blocked BMP-mediated anti-proliferation and expression of contractile marker genes in HPAMSCs, suggesting that the expression and functional activity of KCNK3 are required for BMP-mediated acquisition of the quiescent PASMC phenotype. Overall, our findings show a crosstalk between BMP signaling and KCNK3 in regulating the PASMC phenotype, wherein BMPs upregulate KCNK3 expression and KCNK3 then mediates BMP-induced phenotypic switching of PASMCs. Our results indicate that the dysfunction and/or downregulation of BMPR2 and KCNK3 observed in PAH work together to induce aberrant changes in the PASMC phenotype, providing insights into the complex molecular pathogenesis of PAH.

• Clinical and Experimental Reproductive Medicine
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• 제48권3호
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• pp.245-254
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• 2021

Objective: In humans, polycystic ovary syndrome (PCOS) is an androgen-dependent ovarian disorder. Aberrant gene expression in folliculogenesis can arrest the transition of preantral to antral follicles, leading to PCOS. We explored the possible role of altered gene expression in preantral follicles of estradiol valerate (EV) induced polycystic ovaries (PCO) in a mouse model. Methods: Twenty female balb/c mice (8 weeks, 20.0±1.5 g) were grouped into control and PCO groups. PCO was induced by intramuscular EV injection. After 8 weeks, the animals were killed by cervical dislocation. Blood serum (for hormonal assessments using the enzyme-linked immunosorbent assay technique) was aspirated, and ovaries (the right ovary for histological examinations and the left for quantitative real-time polymerase) were dissected. Results: Compared to the control group, the PCO group showed significantly lower values for the mean body weight, number of preantral and antral follicles, serum levels of estradiol, luteinizing hormone, testosterone, and follicle-stimulating hormone, and gene expression of TGFB1, GDF9 and BMPR2 (p<0.05). Serum progesterone levels were significantly higher in the PCO animals than in the control group (p<0.05). No significant between-group differences (p>0.05) were found in BMP6 or BMP15 expression. Conclusion: In animals with EV-induced PCO, the preantral follicles did not develop into antral follicles. In this mouse model, the gene expression of TGFB1, GDF9, and BMPR2 was lower in preantral follicles, which is probably related to the pathologic conditions of PCO. Hypoandrogenism was also detected in this EV-induced murine PCO model.

• Molecules and Cells
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• 제37권9호
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• pp.691-698
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• 2014

SCYL1-BP1 is thought to function in the p53 pathway through Mdm2 and hPirh2, and mutations in SCYL1-BP1 are associated with premature aging syndromes such as Geroderma Osteodysplasticum; however, these mechanisms are unclear. Here, we report significant alterations in miRNA expression levels when SCYL1-BP1 expression was inhibited by RNA interference in HEK293T cells. We functionally characterized the effects of potential kernel miRNA-target genes by miRNA-target network and protein-protein interaction network analysis. Importantly, we showed the diminished SCYL1-BP1 dramatically reduced the expression levels of EEA1, BMPR2 and BRCA2 in HEK293T cells. Thus, we infer that SCYL1-BP1 plays a critical function in HEK293T cell development and directly regulates miRNA-target genes, including, but not limited to, EEA1, BMPR2, and BRCA2, suggesting a new strategy for investigating the molecular mechanism of SCYL1-BP1.

• Molecules and Cells
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• 제37권3호
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• pp.270-274
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• 2014

Lymphatic vessels are essential to regulate interstitial fluid homeostasis and diverse immune responses. A number of crucial factors, such as VEGFC, SOX18, PROX1, FOX2C, and GJC2, have been implicated in differentiation and/or maintenance of lymphatic endothelial cells (LECs). In humans, dysregulation of these genes is known to cause lymphedema, a debilitating condition which adversely impacts the quality of life of affected individuals. However, there are no currently available pharmacological treatments for lymphedema, necessitating identification of additional factors modulating lymphatic development and function which can be targeted for therapy. In this report, we investigate the function of genes associated with Bone Morphogenetic Protein (BMP) signaling in lymphatic development using zebrafish embryos. The knock-down of BMP type II receptors, Bmpr2a and Bmpr2b, and type I receptors, Alk3 and Alk3b, as well as SMAD5, an essential cellular mediator of BMP signaling, led to distinct lymphatic defects in developing zebrafish. Therefore, it appears that each constituent of the BMP signaling pathway may have a unique function during lymphatic development. Taken together, our data demonstrate that BMP signaling is essential for normal lymphatic vessel development in zebrafish.